This is a competitive renewal application for P01 AG004875, Physiology of Bone Metabolism in an Aging Population. Osteoporosis is an enormous public health problem, and our overall goal is to better understand the mechanisms and consequences of bone loss with aging. As in the past, the major strength of our group is to bring together diverse disciplines into synergistic interactions, and the present application includes population-based epidemiology studies, intensive studies in the Clinical Research Unit (formerly the General Clinical Research Center), animal studies using novel mouse models, and basic cellular and molecular studies. Using this integrated approach, we propose to focus on three major areas: (1) Defining the mechanisms by which estrogen (E) regulates bone metabolism; (2) With increases in bone resorption, as in the setting of E deficiency, identifying the mechanisms by which osteoclasts regulate osteoblasts; and (3) Assessing the risk factors for and consequences of fractures that increase with E deficiency and with aging. Each of the Projects are aligned with one or more of these major themes: Project 1 (Pathophysiology of Osteoporosis) uses the human as the experimental model to address key, unresolved issues regarding E action on bone, including definitively establishing whether follicle-stimulating hormone modulates bone resorption in the setting of E deficiency and defining mechanisms for the age-related decrease in bone formation; Project 2 (Risk Factors for Fractures Among the Elderly) provides a population perspective on risk factors for fractures (secondary osteoporosis) that exacerbate bone loss with E deficiency and with aging; Project 3 (Osteoclast Regulation of Bone Formation) pursues the basic biology and functional relevance of factors made by osteoclasts that regulate bone formation; and Project 4 (Estrogen Receptor Signaling Pathways in Bone) uses in vitro and novel mouse models to dissect E signaling pathways in bone. A single Core (Administrative and Biostatistics Core) provides the necessary infrastructure to support these Projects. Collectively, these studies strive to provide a comprehensive assesment of the pathogenesis and clinical impact of one of the most important disorders facing our aging population.